: The objective of this proposal is to examine the role of endothelin B receptors in modulating renal-pressure natriuresis and blood pressure regulation. In 1988, Yanagsawa and co-workers characterized an endothelial-derived peptide subsequently called endothelin (El). Two major subtypes of endothelin receptors have been characterized, ETA and ETB receptors. Both of these receptors are located in the kidney with the highest concentration of ETB receptors occurring within the medulla. Although the role of ETA receptors have been well characterized in the pathophysiology of hypertension, the physiological importance of ETB receptors in modulating renal-pressure natriuresis and blood pressure regulation is unclear. Preliminary data from our laboratory indicates that the renal production of El is enhanced by chronic Na loading. Moreover, data from our laboratory indicates that chronic ETB receptor blockade results in a Na-sensitive form of hypertension. The exact mechanisms involved in mediating the hypertension induced by chronic ETB receptor blockade, however, are unknown. Specific aims to be addressed are: 1) To test the hypothesis that the ET system is upregualted in response to increases in Na intake 2) To test the hypothesis that the hypertension induced by chronic ETB receptor blockade is associated with a chronic hypertensive shift in the pressure-natriuresis relationship 3) to test the hypothesis that determine the renal medulla plays an important role in mediating the hypertension induced by chronic ETB receptor blockade 4) To test the hypothesis that reduced nitric oxide synthesis mediates the reduction in renal function and elevation in arterial pressure during ETB receptor blockade-induced hypertension.